Novel 1,2-Dithiins: Synthesis, Molecular Modeling Studies, and Antifungal Activity

The first structure-activity study involving the 1,2-dithiin class of compounds (1,2-dithiacyclohexadienes) is herein reported. A series of 3,6-disubstituted 1,2-dithiins was synthesized from dithiins 1d and 1e and evaluated as antifungal agents. A new and versatile synthesis of dithiins 1d and 1e i...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-07, Vol.38 (14), p.2628-2648
Main Authors: Bierer, Donald E, Dener, Jeffrey M, Dubenko, Larisa G, Gerber, R. Eric, Litvak, Joane, Peterli, Stefan, Peterli-Roth, Patricia, Truong, Thien V, Mao, Guohua, Bauer, Barr E
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antifungal agents
Antifungal Agents - chemical synthesis
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
Aspergillus fumigatus
Aspergillus fumigatus - drug effects
Biological and medical sciences
Candida albicans
Candida albicans - drug effects
Chemistry
Cryptococcus neoformans
Cryptococcus neoformans - drug effects
Exact sciences and technology
Heterocyclic compounds
Heterocyclic Compounds - chemical synthesis
Heterocyclic Compounds - chemistry
Heterocyclic Compounds - pharmacology
Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives
Magnetic Resonance Spectroscopy
Medical sciences
Microbial Sensitivity Tests
Models, Molecular
Organic chemistry
Pharmacology. Drug treatments
Preparations and properties
Structure-Activity Relationship
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Summary:The first structure-activity study involving the 1,2-dithiin class of compounds (1,2-dithiacyclohexadienes) is herein reported. A series of 3,6-disubstituted 1,2-dithiins was synthesized from dithiins 1d and 1e and evaluated as antifungal agents. A new and versatile synthesis of dithiins 1d and 1e is reported which is amenable to scale-up at the kilogram level. The novelty of the process derives from the use of beta-mercaptopropionitrile as the thiophile, relying on a beta-elimination strategy and subsequent oxidation to create the 1,2-dithiin ring. Optimal geometries of dithiins 1d, 18i, and 45 and model dithiin 61 were determined by molecular mechanics and Hartree-Fock molecular orbital calculations. Two possible mechanisms of action are presented for the 1,2-dithiin class of compounds to explain their observed antifungal activities against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00014a016